Germline KRAS mutations cause Noonan syndrome

Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage-specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.     

Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in ～50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.     

Cycling or not cycling: cell cycle regulatory molecules and adult neurogenesis

The adult brain most probably reaches its highest degree of plasticity with the lifelong generation and integration of new neurons in the hippocampus and olfactory system. Neural precursor cells (NPCs) residing both in the subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles continuously generate neurons that populate the dentate gyrus and the olfactory bulb, respectively. The regulation of NPC proliferation in the adult brain has been widely investigated in the past few years. Yet, the intrinsic cell cycle machinery underlying NPC proliferation remains largely unexplored. In this review, we discuss the cell cycle components that are involved in the regulation of NPC proliferation in both neurogenic areas of the adult brain.     

Using human pluripotent stem cells to untangle neurodegenerative disease mechanisms

Human pluripotent stem cells, including embryonic (hES) and induced pluripotent stem cells (hiPS), retain the ability to self-renew indefinitely, while maintaining the capacity to differentiate into all cell types of the nervous system. While human pluripotent cell-based therapies are unlikely to arise soon, these cells can currently be used as an inexhaustible source of committed neurons to perform high-throughput screening and safety testing of new candidate drugs. Here, we describe critically the available methods and molecular factors that are used to direct the differentiation of hES or hiPS into specific neurons. In addition, we discuss how the availability of patient-specific hiPS offers a unique opportunity to model inheritable neurodegenerative diseases and untangle their pathological mechanisms, or to validate drugs that would prevent the onset or the progression of these neurological disorders.     

Earthworms (Annelida: Oligochaeta) from islands of Kien Hai District,Kien Giang Province,Vietnam, with descriptions of two new species and one subspecies

An earthworm inventory was conducted on three islands (Hon Tre, Lai Son and An Son) in the southernmost part of Vietnam. A total of 13 species and subspecies belonging to four genera and two families were collected from 49 sampling sites. The genus Metaphire Sims & Easton, 1972 is dominant with six species and subspecies, Metaphire anomala (Michaelsen, 1907), Metaphire bahli (Gates, 1945), Metaphire houlleti (Perrier, 1872), Metaphire mangophila (Nguyen, 2011), Metaphire kiengiangensis Nguyen & Trinh, 2015, Metaphire peguana laisonensis subsp. nov. Two new species, Polypheretima dorsotheca sp. anov. and Polypheretima insularis sp. nov., and a new subspecies Metaphire peguana laisonensis subsp. nov. are described. Additionally, Amynthas alteradamae (Michaelsen, 1934) and Amynthas tertiadamae (Michaelsen, 1934) are re-described based on fresh material. An identification key to species is also provided.

http://zoobank.org/urn:lsid:zoobank.org:pub:4EA4C2C0-BEC2-45BF-8B72-388302A53F51     

An electrochemical and microstructural characterization of steel-mortar admixed with corrosion inhibitors

The present research brings new insights on the role of admixed corrosion inhibitors in the processes of cement hydration and rebar corrosion.The admixing of NaCl and the corrosion inhibitors in fresh mortar was found to alter the morphology and microstructure of the hardened mortar at the steel-mortar interfacial region.The admixing of the inhibitors increased the risk of carbonation of cement hydrates at the steel-mortar interfacial region,but partially displaced chloride ions. Chloride and the admixed in...     

Modeling and forecasting commodity market volatility with long-term economic and financial variables

This paper investigates the time-varying volatility patterns of some major commodities as well as the potential factors that drive their long-term volatility component. For this purpose, we make use of a recently proposed generalized autoregressive conditional heteroskedasticity–mixed data sampling approach, which typically allows us to examine the role of economic and financial variables of different frequencies. Using commodity futures for Crude Oil (WTI and Brent), Gold, Silver and Platinum, as well as a commodity index, our results show the necessity for disentangling the short-term and long-term components in modeling and forecasting commodity volatility. They also indicate that the long-term volatility of most commodity futures is significantly driven by the level of global real economic activity as well as changes in consumer sentiment, industrial production, and economic policy uncertainty. However, the forecasting results are not alike across commodity futures as no single model fits all commodities.